Latency of Epstein–Barr virus is disrupted by gain-of-function mutant cellular AP-1 proteins that preferentially bind methylated DNA

Yu, Kuan Ping; Heston, Lee; Ding, Zhaowei; Wang’ondu, Ruth; Delecluse, Henri Jacques; Miller, George

doi:10.1073/pnas.1301577110

Cited by 17 publications

(27 citation statements)

References 41 publications

(26 reference statements)

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“…While such methylated bases inhibit most transcription factors from activating gene expression, the Z protein actually has a preference for the methylated forms of many viral and cellular promoters [25,73,86–90]. Z binding to methylated ZREs requires serine residue 186 located within its DNA-binding domain [87,91]; the equivalent position in c-Jun and c-fos contains an alanine residue. Conversion of these alanines to serines enables these latter proteins to also activate methylated Rp [91].…”

Section: Role Of Genome Methylationmentioning

confidence: 99%

“…Z binding to methylated ZREs requires serine residue 186 located within its DNA-binding domain [87,91]; the equivalent position in c-Jun and c-fos contains an alanine residue. Conversion of these alanines to serines enables these latter proteins to also activate methylated Rp [91]. Z’s unique ability to activate methylated promoters helps to ensure rapid EBV reactivation following Z synthesis, despite the EBV genome being methylated in most latently infected cells (Fig.…”

Section: Role Of Genome Methylationmentioning

confidence: 99%

“…3). Nevertheless, maximal lytic-gene expression and genome replication requires both Z and R regardless of the methylation status of the viral genome [25,91]. This synergy is achieved, in part, by Z and R activating each other’s promoters.…”

Section: Role Of Genome Methylationmentioning

confidence: 99%

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Regulation of the latent-lytic switch in Epstein–Barr virus

Kenney

Mertz

2014

Seminars in Cancer Biology

233

235

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Epstein–Barr virus (EBV) infection contributes to the development of several different types of human malignancy, including Burkitt lymphoma, Hodgkin lymphoma, and nasopharyngeal carcinoma. As a herpesvirus, EBV can establish latent or lytic infection in cells. EBV-positive tumors are composed almost exclusively of cells with latent EBV infection. Strategies for inducing the lytic form of EBV infection in tumor cells are being investigated as a potential therapy for EBV-positive tumors. In this article, we review how cellular and viral proteins regulate the latent-lytic EBV switch in infected B cells and epithelial cells, and discuss how harnessing lytic viral reactivation might be used therapeutically.

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Section: Role Of Genome Methylationmentioning

confidence: 99%

Section: Role Of Genome Methylationmentioning

confidence: 99%

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Regulation of the latent-lytic switch in Epstein–Barr virus

Kenney

Mertz

2014

Seminars in Cancer Biology

233

235

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“…11,13). Z (also known as EB1, ZEBRA, and Zta) is a bZip protein homologous to AP-1 and binds to AP-1-like sites (Z-responsive elements, ZREs) that often contain CpG motifs (11,(13)(14)(15). Once established, EBV genome methylation is maintained during latent viral genome replication (licensed and mediated by host cell replication machinery) via the enzymatic activity of DNA methyltransferases (1,2).…”

mentioning

confidence: 99%

5-hydroxymethylation of the EBV genome regulates the latent to lytic switch

Wille

Nawandar

Henning

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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Latent Epstein-Barr virus (EBV) infection and cellular hypermethylation are hallmarks of undifferentiated nasopharyngeal carcinoma (NPC). However, EBV infection of normal oral epithelial cells is confined to differentiated cells and is lytic. Here we demonstrate that the EBV genome can become 5-hydroxymethylated and that this DNA modification affects EBV lytic reactivation. We show that global 5-hydroxymethylcytosine (5hmC)-modified DNA accumulates during normal epithelial-cell differentiation, whereas EBV+ NPCs have little if any 5hmC-modified DNA. Furthermore, we find that increasing cellular ten-eleven translocation (TET) activity [which converts methylated cytosine (5mC) to 5hmC] decreases methylation, and increases 5hmC modification, of lytic EBV promoters in EBV-infected cell lines containing highly methylated viral genomes. Conversely, inhibition of endogenous TET activity increases lytic EBV promoter methylation in an EBV-infected telomerase-immortalized normal oral keratinocyte (NOKs) cell line where lytic viral promoters are largely unmethylated. We demonstrate that these cytosine modifications differentially affect the ability of the two EBV immediateearly proteins, BZLF1 (Z) and BRLF1 (R), to induce the lytic form of viral infection. Although methylation of lytic EBV promoters increases Z-mediated and inhibits R-mediated lytic reactivation, 5hmC modification of lytic EBV promoters has the opposite effect. We also identify a specific CpG-containing Z-binding site on the BRLF1 promoter that must be methylated for Z-mediated viral reactivation and show that TET-mediated 5hmC modification of this site in NOKs prevents Z-mediated viral reactivation. Decreased 5-hydroxymethylation of cellular and viral genes may contribute to NPC formation.EBV | 5hmC | lytic reactivation | NPC

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“…It has been demonstrated that a methylated EBV genome is essential for viral lytic reproduction (51,53,72), as the immediate-early protein Zta preferentially binds to methylated viral promoters (54,(73)(74)(75). In 293T cells stably infected with an EBV genome, high occupancies of Zta were observed in methylated promoters of BALF2, BMRF1, Rta, and BHLF1, whereas these bindings were disrupted once the EBV genome is hypomethylated (54).…”

Section: Discussionmentioning

confidence: 97%

Epstein-Barr Virus Rta-Mediated Accumulation of DNA Methylation Interferes with CTCF Binding in both Host and Viral Genomes

Chen

Chang

et al. 2017

J Virol

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Rta, an Epstein-Barr virus (EBV) immediate-early protein, reactivates viral lytic replication that is closely associated with tumorigenesis. In previous studies, we demonstrated that in epithelial cells Rta efficiently induced cellular senescence, which is an irreversible G 1 arrest likely to provide a favorable environment for productive replications of EBV and Kaposi's sarcoma-associated herpesvirus (KSHV). To restrict progression of the cell cycle, Rta simultaneously upregulates CDK inhibitors and downregulates MYC, CCND1, and JUN, among others. Rta has long been known as a potent transcriptional activator, thus its role in gene repression is unexpected. In silico analysis revealed that the promoter regions of MYC, CCND1, and JUN are common in (i) the presence of CpG islands, (ii) strong chromatin immunoprecipitation (ChIP) signals of CCCTC-binding factor (CTCF), and (iii) having at least one Rta binding site. By combining ChIP assays and DNA methylation analysis, here we provide evidence showing that Rta binding accumulated CpG methylation and decreased CTCF occupancy in the regulatory regions of MYC, CCND1, and JUN, which were associated with downregulated gene expression. Stable residence of CTCF in the viral latency and reactivation control regions is a hallmark of viral latency. Here, we observed that Rta-mediated decreased binding of CTCF in the viral genome is concurrent with virus reactivation. Via interfering with CTCF binding, in the host genome Rta can function as a transcriptional repressor for gene silencing, while in the viral genome Rta acts as an activator for lytic gene loci by removing a topological constraint established by CTCF.IMPORTANCE CTCF is a multifunctional protein that variously participates in gene expression and higher-order chromatin structure of the cellular and viral genomes. In certain loci of the genome, CTCF occupancy and DNA methylation are mutually exclusive. Here, we demonstrate that the Epstein-Barr virus (EBV) immediate-early protein, Rta, known to be a transcriptional activator, can also function as a transcriptional repressor. Via enriching CpG methylation and decreasing CTCF reloading, Rta binding efficiently shut down the expression of MYC, CCND1, and JUN, thus impeding cell cycle progression. Rta-mediated disruption of CTCF binding was also detected in the latency/reactivation control regions of the EBV genome, and this in turn led to viral lytic cycle progression. As emerging evidence indicates that a methylated EBV genome is a preferable substrate for EBV Zta, the other immediate-early protein, our results suggest a mechanistic link in understanding the molecular processes of viral latent-lytic switch.KEYWORDS Epstein-Barr virus, immediate-early protein Rta, lytic cycle reactivation, CTCF, DNA methylation, cell cycle arrest, genome topology, immediate-early protein Rta

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Latency of Epstein–Barr virus is disrupted by gain-of-function mutant cellular AP-1 proteins that preferentially bind methylated DNA

Cited by 17 publications

References 41 publications

Regulation of the latent-lytic switch in Epstein–Barr virus

Regulation of the latent-lytic switch in Epstein–Barr virus

5-hydroxymethylation of the EBV genome regulates the latent to lytic switch

Epstein-Barr Virus Rta-Mediated Accumulation of DNA Methylation Interferes with CTCF Binding in both Host and Viral Genomes

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